These days, social media is full of posts by both legitimate and self-proclaimed health experts describing new supplements or lifestyle hacks that promise health, strength, and longevity. Maybe it is the aging population, frustration with the medical establishment, or the ready access to (mis)information that is driving this. 

Sometimes this information is sound (that is, it is backed by research), but often it is not and is promoted by people who have a financial interest. In many cases, it is pseudoscience. Information presented with a lot of scientific jargon but lacking actual scientific rigor. 

In this article, I will review the current interest in NAD+ and its relationship to aging and disease, including the results of animal vs human studies.

NAD+ stands for nicotinamide adenine dinucleotide. This molecule contains nicotinamide, which is a form of vitamin B3 (niacin), Adenine, which is one of the building blocks of DNA, and Dinucleotide, which means it is made of two linked nucleotides, which are small molecules that store and transfer energy. 

The reason NAD is often followed by a + sign is that this coenzyme has a net positive charge, meaning it can pick up electrons in electron transfer during oxidation–reduction reactions in mitochondria to generate ATP. 

In addition to its function in energy production, it is also involved in DNA repair, cell senescence and clearing of old cells, and signaling within the cell that turns genes on or off when a receptor is activated, cell growth and division, inflammation, lipid and glucose homeostasis. 

NAD+ is known to be involved in over 500 enzymatic reactions in the cell. So clearly, an important molecule for life and health.

NAD⁺ levels typically decline with age, potentially impairing mitochondrial function, DNA repair, and cellular stress responses. This is what has led to an interest in raising NAD+ via supplementing with NAD+ precursors. 

These supplements include Nicotinamide Mononucleotide (NMN), Nicotinamide Riboside (NR), and Niacin, which are all different forms of the vitamin B3. Many animal studies show these molecules have benefits. NMN has more studies suggesting vascular and muscle function benefits; NR has more studies on neuroprotection and metabolism.

In human studies, mostly completed in vitro (tissue cultures not in a living person), NR and NMN supplementation has shown NAD+ increases. In Vivo studies in living people show increases in NAD+ also. In these short term studies, correlation with improved clinical outcomes are not consistently seen and long-term safety information is lacking.  

NR has been accepted as a dietary supplement for years by the FDA, and interestingly, the FDA had withdrawn supplement approval for NMN previously but just classified NMN as lawful for use in dietary supplements in 2025.

This is not the same as FDA “approval” of NMN as a drug. The FDA did not approve NMN or NR to treat or prevent disease; the decision is only about their status as supplement ingredients.

You may be more familiar with niacin, one of the oldest forms of B3. This vitamin has been used to lower cholesterol and maintain NAD+ levels. It is safe in small doses but is known to cause transient flushing of the skin, which can be quite uncomfortable in doses above 50mg.

In high doses, such as 1-3 g per day, it can also cause liver enzyme elevations, insulin resistance, GI upset, and increased risk of gout. 

Nicotinamide is a form of B3 that is not associated with flushing. In small clinical studies, higher dose oral nicotinamide has been shown to raise blood NAD⁺ or NADH modestly, but not as dramatically as NR or NMN. 

However, the higher dosage used to get NAD+ elevations, can cause side effects such as fatigue, nausea, headaches, liver inflammation, insulin resistance, and GI upset.

Another compound that is generating interest is Fisetin, which is a plant-based flavonol found naturally in strawberries, apples, onions, and cucumbers. It’s similar to quercetin (another flavonoid) but has unique biological activities that have drawn attention in aging and longevity research. 

Over time, senescent cells, which are older or damaged cells, don’t die when they should. They accumulate and release inflammatory molecules. This chronic low-grade inflammation contributes to tissue dysfunction, frailty, and many age-related diseases. 

Fisetin is considered a senolytic, that is, it can selectively trigger the death of senescent cells. Removing these cells in animal models has been shown to improve tissue function and extend lifespan. In vivo studies in humans are ongoing in early-phase trials in aging osteoarthritis, frailty, and sepsis prevention. The FDA has made it legal as a supplement, but not as a drug that can treat or prevent disease.

Fisetin has promise, but its senolytic and clinical effects in humans remain unproven. In humans, safe and effective dosages and long-term effects are not known at this time. While animal data are compelling, we don’t yet know if fisetin clears senescent cells in people, improves healthspan, or is even safe in the long term. We await the results of the ongoing trials.

In summary, NAD+ precursors and Fisetin, which are promoted for health and longevity by social influencers, have yet to be conclusively proven through scientific in vivo studies in humans. Many questions remain unanswered, especially safety; a low dose that might result in beneficial effects, but a high (over)dose might induce an inhibitory or even toxic effect. 

Also, which diseases should be targeted with this treatment? What about drug interactions? And what unintended consequences could result, such as an increased risk of cancer? 

As an example of unintended consequences, consider Beta-Carotene (a precursor to vit A found in carrots and other veggies). This supplement was promoted to reduce the risk of lung cancer and heart disease in the 1980s because studies showed people who ate more fruits and vegetables had lower rates of lung cancer. 

This led to large trials testing beta-carotene pills as a preventive supplement. However, the studies showed that beta-Carotene supplementation actually significantly increased lung cancer risk! 

In healthy amounts from foods, beta-carotene acts as an antioxidant. But in the oxidative environment of smokers’ lungs, high doses of synthetic beta-carotene likely acted as a pro-oxidant, damaging DNA and promoting cancer growth. It was a striking case where isolating and over-supplementing one “beneficial” compound had the opposite effect.

Longevity supplements like NAD+ precursors and Fisetin may indeed turn out to be of great benefit for certain populations when dosed correctly, but might turn out to be not helpful or even risky in the long term. We need more evidence regarding benefit and risk. 

Cell biology is incredibly complex. A cell isn’t a machine with a single switch. Most molecules are multifunctional, participating in many unrelated processes. This is why interventions that seem simple, like raising NAD+, could have unintended consequences. 

Artificially pushing NAD⁺ too high may drain precursors needed elsewhere, possibly causing metabolic stress.That’s why researchers emphasize context, dose, and duration in NAD⁺-boosting strategies, and why “more” is not automatically “better.”

Where does this leave us? As is often the case, many supplements such as vitamins, are already present in healthy foods such as fruits and vegetables, in quantities that are known to be healthy for consumption.

A plant-forward diet, consistent and adequate sleep, regular exercise, meaningful social connections, and stress management are all well-researched and have been clearly shown to promote health and longevity. That is a good place to start.